Type 2 diabetes mellitus has become a worldwide epidemic with significant human and economic burdens. Diabetic patients are particularly at risk of mortality from myocardial infarction and it is therefore important that glucose lowering is achieved by drugs that do not further compromise the heart. Evidence now supports Ca2+/calmodulin-dependent protein kinase II (CaMKII), a mediator Ca2+ signaling in liver and heart, as a novel target for inhibitors with the unique dual action of lowering glucose while providing cardioprotection. Genetic approaches have rigorously demonstrated that a CaMKII-p38a-MK2/3 pathway mediates the action of glucagon on glucose production in liver while a CaMKII-Ryanodine receptor pathway underlies dysregulated Ca2+ signaling in heart. Genetic suppression of CaMKII lowers blood glucose, and decreases progression from hypertrophy to heart failure and arrhythmia, while its hyperactivity increases blood glucose and promotes heart disease. We propose to advance our highly selective allosteric small molecule CaMKII inhibitors via lead optimization and test the feasibility that they lower hepatic glucose production. Activated CaMKII is prone to pathological hyperactive states in diabetes, due to oxidation and other post-translational modifications, all of which are blocked by our allosteric inhibitors. We propose a structure-based medicinal chemistry strategy of lead optimization to increase inhibitor potency and limit any CNS penetration while retaining their high kinase selectivity. We will evaluate their biochemical and cellular properties to ensure they have the desired characteristics prior to a mechanistic POC in lowering hepatic glucose output in ob/ob mice. Successful completion of our Phase I milestones will set a clear path for a Phase II proposal to further advance its pharmacokinetics and other drug-like properties and extend the proof-of-concept for cardioprotection and long-term glucose control. Pharma and venture capitalists have shown significant interest in our allosteric CaMKII inhibitor program?their funding is dependent on achieving a more advanced lead compound that does not affect brain CaMKII while showing preclinical efficacy in glucose control. Our proposed studies and an SBIR award will position the program for funding or a partnership to advance through IND enabling studies and an IND.